N-[2-(7-lower-alkoxynaphth-1-yl)ethyl]benzamides

ABSTRACT

Compounds of the formula: ##STR1## in which: A represents ##STR2## R represents linear or branched lower alkyl, R 1  represents hydrogen or linear or branched lower alkyl, and 
     R 2  represents aryl or lower arylalkyl or aryl or lower arylalkyl substituted by lower alkyl, lower alkoxy, trifluoromethyl, or halogen, aryl means phenyl or naphthyl, as well as optical isomers, epimers and diastereoisomers and addition salts thereof with a pharmaceutically-acceptable acid, lower alkyl and lower alkoxy having 1 to 6 carbon atoms inclusive, and 
     medicaments containing the same which are useful for the treatment of disorders of the melatoninergic system.

The present application is a division of our prior-filed copendingapplication Ser. No. 07/816,466 filed Jan. 3, 1992, now U.S. Pat. No.5,225,442, issued Jul. 6, 1993, which is in turn a division of Ser. No.07/661,425, filed Feb. 26, 1991, now U.S. Pat. No. 5,194,614, issuedMar. 16, 1993.

present invention concerns new compounds of1-alkoxy-(2-acylaminoethyl)naphthalenes, a process for preparing theseand pharmaceutical compositions containing them.

A certain number of (2-aminoethyl)naphthalenes have been describedpreviously. Patent Application JP 50-089352 describes naphthalenederivatives having antipyretic, anti-inflammatory and analgesicactivity. Patent Application JP 61-282348 describes(arylalkylamino-alkyl) naphthalenes as fungicidal agents. U.S. Pat. No.4,327,022 describes aminoalkyldialkoxy-naphthalenes as fungicides.Patent Application EP 149,588 describes(hydroxyaminoalkyl)-methoxynaphthalenes as inhibitors of lipoxygenaseand therefore useful for treating asthma, inflammation and psoriasis.Patent Application FR 70.44709 describes 1-phenyl-2-[2-naphth-1-yl)ethylamino]-ethanols as anti-spasmodics and vasodilators.

The applicant company has now discovered that new derivatives of1-alkoxy-(2-acylaminoethyl)naphthalenes possess valuable pharmacologicalproperties with regard to the central nervous system, particularlyanxiolytic, antipsychotic and analgesic properties, and with regard toovulation, cerebral circulation, immunomodulation, and are clearlydistinguished from the aminoalkylnaphthalene compounds described above.

The subject of the invention is, more especially, the compounds, ofgeneral formula (I): ##STR3## in which A represents a ##STR4## Rrepresents a linear or branched lower alkyl group, R₁ represents ahydrogen atom or a linear or branched lower alkyl group, and

R₂ represents

a hydrogen atom,

a linear or branched lower alkyl group or a cycloalkyl group optionallysubstituted by a halogen atom,

an aryl or heteroaryl or lower arylalkyl or substituted aryl orsubstituted heteroaryl or substituted arylalkyl group, it beingunderstood that by heteroaryl group is understood an unsaturated mono-or bicyclic group including 1 to 3 heteroatoms chosen from amongnitrogen, oxygen or sulfur,, with each ring comprising 4 or 5 apexes,and that by aryl group is understood phenyl or naphthyl,

an imidazolyl group optionally reduced and/or substituted by an oxogroup,

a group of formula: ##STR5## where G represents a linear or branchedlower alkyl group, and R₃ and R₄, identical or different, both representa lower alkyl group or a hydrogen atom or a phenyl or lower phenylalkylgroup, or R₃ and R₄ form, with the nitrogen atom to which they areattached, a mono- or bicyclic heterocyclic system which may or may notbe aromatic, with each ring having five or six apexes optionallyincluding another heteroatom and being optionally substituted by one ormore lower alkyl, or oxo, aryl or lower arylalkyl, or substituted arylor substituted lower arylalkyl groups, it being understood that the termsubstituted qualifying the aryl and arylalkyl, and heteroaryl, groups inthe definition of R₂, R₃ and R₄ means that these groups are substitutedby one or more radicals chosen from among lower alkyl, lower alkoxy,trifluoromethyl or a halogen atom, or R₁ forms with R₂ and the N-COgroup a heterocyclic system of formula: ##STR6## with A being a linearor branched alkyl radical comprising 2 to 8 carbon atoms, their isomers,epimers and diastereoisomers as well as, if the case arises, theiraddition salts with a pharmaceutically acceptable acid, it beingunderstood that lower alkyl and lower alkoxy mean groups comprising 1 to6 carbon atoms and that cycloalkyl means groups comprising 3 to 8 carbonatoms.

Among the pharmaceutically acceptable acids which can, if the casearises, be added to compounds of formula (I) to obtain a salt there maybe mentioned, without implied limitation, hydrochloric, sulfuric,tartaric, maleic, fumaric, oxalic, methanesulfonic and camphoric acids,etc.

The subject of the present invention is also a process for preparingcompounds of formula (I), which comprises using as starting material acompound of formula (II): ##STR7## in which R and R₁ have the samemeaning as in formula (I) , which is treated

either with a compound of formula (III): ##STR8## in which E means astarting group chosen from among hydroxyl, lower alkoxy or a halogen,and G, R₃ and R₄ have the same meaning as in formula (I) , optionally inthe presence of an alkaline agent, to lead to a compound of formula(I/A), a particular case of compounds. of formula (I): ##STR9## in whichR, R₁, R₃, R₄ and G have the same definition as above,

R₂ here meaning a group ##STR10## which can be purified, if so desired,by conventional techniques such as chromatography and crystallization,and which can be converted into a salt, if so desired, by apharmaceutically acceptable acid,

or with an acyl chloride of formula (IV):

    Cl--CO--R'.sub.2                                           (IV)

or with the corresponding acid anhydride,

R'₂ here meaning

a linear or branched lower alkyl group or a cycloalkyl group optionallysubstituted by a halogen atom,

an aryl or heteroaryl or lower arylalkyl group, optionally substitutedby one or more halogen atoms or groups chosen from among lower alkyl,lower alkoxy or trifluoromethyl,

an imidazolyl group optionally reduced and/or substituted by an oxogroup,

to lead to a compound of formula (I/B): ##STR11## a particular case ofcompounds of formula (I) in which R, and R'₂ have the same def initionas above, which can be purified, if necessary, by conventionaltechniques such as chromatography and/or crystallization,

when R'₂ represents a linear or branched lower alkyl group substitutedby a halogen atom, a compounds of formula (I/B) which, can be subjected,if so desired, to the action of an amine of formula (V): ##STR12## inwhich R₃ and R₄ have the same definition as above, in excess or in thepresence of a tertiary amine or of a salt of an alkali metal, to lead toa compound of formula (I/A) as defined above, which, if so desired, ispurified by a conventional technique such as chromatography and/orcrystallization, and/or converted into a salt by a pharmaceuticallyacceptable acid,

a compound of formula (I/B) which, when R'₂ represents a linear orbranched alkyl substituent comprising at least two carbon atoms andsubstituted by a halogen atom, and when simultaneously R₁ represents ahydrogen atom, can be subjected, if so desired, to the action of astrong base, and preferably an alcoholate of an alkali metal, to lead toa compound of formula (I/C): ##STR13## in which R has the same meaningas above and A represents a linear or branched alkyl group comprising 2to 8 carbon atoms, a particular case of compounds of formula (I) forwhich R₁ and R₂ form With NCO a monocyclic system substituted by an oxogroup, and optionally substituted by one or more lower alkyl groups,

which is purified, if so desired, by a technique chosen from amongcrystallization and chromatography.

The compounds of formula (I) possess valuable pharmaceutical properties.

Pharmacological study of the compounds s of the invention in fact showedthat they have low toxicity, that they are endowed with a very highselective affinity for melatonin receptors, and that they have majoreffects on the central nervous system, and in particular sedative,anxiolytic, antipsychotic and analgesic properties have been revealed,as well as on the microcirculation which enable us to claim that theproducts of the invention are useful in the treatment of stress, sleepdisorders, anxiety, seasonal depression, insomnia and tiredness due to"jet lag", schizophrenia, panic attacks, melancholy, the regulation ofappetite, insomnia, psychotic problems, epilepsy, Parkinson's disease,senile dementia, the various disorders resulting from normal orpathological ageing, migraine, memory loss, Alzheimer's disease, as wellas disorders of cerebral circulation.

In another field of activity, it appears that the products of theinvention possess properties as inhibitors of ovulation, and asimmunomodulators, and that they can therefore be used in the treatmentof certain cancers and that, administered externally, they are useful inthe treatment of psoriasis, acne, seborrhea, protect the skin andpromote the growth of hair. They can also have a veterinary applicationbecause of their properties in relation to the coat.

The subject of the present invention is also pharmaceutical compositionscontaining the products of formula (I) or, if the case arises, of theiraddition salts with a pharmaceutically acceptable acid, alone or incombination with one or more pharmaceutically acceptable inert non-toxicexcipients or vehicles.

Among the pharmaceutical compositions according to the invention theremay be mentioned, in particular, those which are suitable for oral,parenteral, nasal, per- or transcutaneous, rectal, perlingual, ocular orrespiratory administration, and particularly simple or sugared pills,sublingual tablets, sachets, packets, capsules, glossettes, tablets,suppositories, creams, ointments, dermal gels, phials for oral andinjectable use, and the like.

Dosage varies according to the age and weight of the patient, the routeof administration, the indications for treatment or the treatments withwhich it may be associated, and ranges between 0.1 mg and 1 gram in 24hours.

The following examples illustrate the invention, without limiting it inany way.

The products described in the "preparations" are not part of theinvention. Their description, however, facilitates the realization ofthe compounds. of the invention.

PREPARATION 1: 2-(7-METHOXYNAPHTH-1-YL)ETHYLANINE Stage A: Ethyl(7-Methoxy-1,2,3,4-Tetrahydro-1-Naphthyaphthylidene) Acetate

50 g of 7-methoxy-1-tetralone, 40 g of ethyl bromoacetate and 150 ml ofbenzene are mixed via a dropping funnel. Activated zinc filings (18.6 g)are added to the mixture for the Reformatsky reaction, followed by aniodine crystal. The mixture is heated to 60° C. and then refluxed for 45minutes.

The mixture is hydrolyzed under ice in the presence of hydrochloricacid, extracted with benzene, dried and boiled in the presence of P₂ O₅.It is then filtered and dried.

The residue is used as such in the following step.

Yield: 80%

Stage B : Ethyl (7-Metboxynaphth-1-yl)Acetate

7.35 g of sulfur are mixed with 50 g of ethyl(7-methoxy-1,2,3,4-tetrahydro-1-naphthylidene) acetate and the mixtureis heated at 215° C. for 10 hours. It is then cooled and 300 ml of ethylacetate are added; the mixture is agitated for 30 minutes, filtered andthen dried.

The residue obtained is used as such in the saponification step.

Yield: 70%

Stage C: (7-Methoxynaphth-1-yl)Acetic Acid

A mixture of the ethyl (7-methoxynaphth-1-yl) acetate obtained above in250 ml of a 20% ethanolic sodium hydroxide solution is heated underreflux for 3 hours.

The mixture is dried, and the residue is washed in ether andprecipitated by a current of hydrogen chloride gas.

Melting point: 155°-156° C.

Yield: 68%

Stage D: (7-Metboxynaphth-1-yl)Acetyl Chloride

The (7-methoxynaphth-1-yl) acetic acid obtained above is dissolved byheating in 300 ml of chloroform. The mixture is heated under reflux, andthen thionyl chloride is added dropwise. The mixture is refluxed for twohours and evaporated to dryness. An oil is obtained which crystallizeson cooling. The residue obtained is used as such in the following stage.

Stage E: (7-Metroxynaphth-1-yl)Acetakide

The (7-methoxynaphth-1-yl)acetyl chloride obtained above is dissolved in200 ml of anhydrous ether. After cooling the solution in an ice/saltbath, 200 ml of concentrated aqueous ammonia solution are added withagitation. The mixture is agitated f or 30 minutes and the precipitate formed is spun down and recrystallized in ethanol.

Yield: 95%

Melting point: 201°-202° C.

Stage F: (7-Methoxynaphth-1-yl)Acetonitrile

The (7-methoxynaphth-1-yl)acetamide obtained in Stage E is suspended in80 ml of anhydrous THF, and triethylamine is added. The solution iscooled in an ice bath, and then trifluoroacetic anhydride is addeddropwise with magnetic agitation. Agitation is continued for one hour atroom temperature. Then the mixture is dried and the residue taken up inwater. The precipitate which forms is spun down, dried andrecrystallized in isopropyl ether.

Yield: 83%

Melting point: 82°-84° C.

Spectral characteristics: Infrared: 2240 cm⁻¹ CN

Stage G: 2-(7-Methoxynaphth-1-yl)Ethylamine

A solution of (7-methoxynaphth-1-yl)acetonitrile in ethanol saturatedwith ammonia is placed in an autoclave. Raney nickel and hydrogen at 300atmospheres are added.

The mixture is agitated at 60° C. overnight and then filtered; thefiltrate is evaporated under vacuum and the oil thus obtained is used asstarting material.

PREPARATION 2: N[2-(7-METHOXYNAPHTH-1-YL)ETHYL]N-METHYLAMINE

The product of the title is obtained by following the same procedure asin Preparation 1, but replacing ammonia by methylamine at Stage E anddirectly reducing the amide so obtained.

PREPARATION 3: 2-(6-METBOXYNAPHTH-1-YL)ETHYLANINE

The product of the title is obtained by following the same procedure asin Preparation 1, but replacing 7-methoxy-1-tetralone by6-methoxy-1-tetralone at Stage A.

PREPARATION 4: 2-(5-METHOXYNAPHTH-1-YL)ETHYLAMINE

The product of the title is obtained by following the same procedure asin Preparation 1, but replacing 7-methoxy-1-tetralone by5-methoxy-1-tetralone at Stage A.

PREPARATION 5: 2-(7-METHOXYNAPHTH-2-YL)ETHYLAMINE

The product of the title is obtained by following the same procedure asin Preparation 1, but replacing 7-methoxy-1-tetralone by7-methoxy-2-tetralone at Stage A.

PREPARATION 6: 2-(6-METHOXYNAPHTH-2-YL)ETHYLAMINE

The product of the title is obtained by f ollowing the same procedure asin Preparation 1, but replacing 7-methoxy-1-tetralone by6-methoxy-2-tetralone at Stage A.

EXAMPLE 1: N-[2-(7-METHOXYNAPHTH-1-YL)ETHYL]ACETAMIDE

0.01 ml of 2-(7-methoxynaphth-1-yl)ethylamine is dissolved in 6 ml ofpyridine. The mixture is cooled in an ice bath with agitation, and 0.012mol of acetyl chloride is added dropwise.

The agitation is maintained for 30 minutes, and then the reaction mediumis poured onto ice. The precipitate formed is spun down, washed, driedand recrystallized in isopropyl ether.

Yield: 92%

Melting point: 109°-110° C.

Spectral characteristics: Infrared: 3240 cm⁻¹ vNH; 1640 cm⁻¹ vCO

¹ H Nuclear magnetic resonance, solvent CDCl₃ : δ: 1.93 ppm, singlet,3H, COCH₃ ; δ: 3.96 ppm, singlet, 3H, OCH₃

EXAMPLE 2: N-[2-(7-METHOXYNAPHTH-1-YL)ETHYL]PHENYLACETAMIDE

0.01 mol of 2-(7-methoxynaphth-1-yl)ethylamine hydrochloride (obtainedby dissolving 2-(7-methoxynaphth-1-yl) ethylamine in ether and bubblingthrough a current of hydrogen chloride gas, then spinning down theprecipitate formed) is dissolved in 60 ml of a water/chloroform mixture.0.01 mol of potassium carbonate is added under magnetic agitation.

The mixture is cooled and 0.012 mol of phenylacetyl chloride is addeddropwise. The agitation is maintained for 30 minutes at roomtemperature, the chloroform phase is dried and the residue isrecrystallized in isopropyl ether.

Yield: 92%

Melting point: 101°-102° C.

Spectral characteristics: Infrared: 3220 cm⁻¹ vNH; 1640 cm⁻¹ vCO

1H Nuclear magnetic resonance, Solvent CDCL₃ : δ: 3.50 ppm, clump, 2H,CH₂ --N; δ: 3.93 ppm, singlet, 1H,, OCH₃

EXAMPLE 3: N-[2-(7-METHOXYNAPTH-1-YL)ETHYL]-ISOBUTYRAMIDE

The product of the title is obtained by following the same procedure asin Example 1, but replacing acetyl chloride by isobutyryl chloride.

Yield: 91%

Melting point: 77°-78° C.

Spectral characteristics: Infrared: 3240 cm⁻¹ vNH; 1640 cm⁻¹ vCO; 1620cm⁻¹ vCC ¹ H Nuclear magnetic resonance, Solvent CDCl₃ : δ: 1.11 ppm,doublet, 6H, 2CH₃ (isopropyl); δ: 2.29 ppm, multiplet, 1H, CH (COCH); δ:3.98 ppm, singlet, 3H, OCH₃

EXAMPLE 4: N-[2-(7-METHOXYNAPHTH-1-YL)ETHYL]-PROPIONAMIDE

The product of the title is obtained by following the same procedure asin Example 1, but replacing acetyl chloride by propionyl chloride.

Melting point: 104°-104.5° C.

EXAMPLE 5: N-[2-(7-METHOXYNAPHTH-1-YL)ETHYL]-PENTANAMIDE

The product of the title is obtained by following the same procedure asin Example 1, but replacing acetyl chloride by pentanoyl chloride.

Crystallising solvent: cylcohexane

Melting point: 90° C.

EXAMPLE 6: N-[2-(7-METHOXYNAPHTH-1-YL)ETHYL]-(2-OXOPYRROLIDIN-1-YL)ACETAMIDE OR1-{2-[(2-OXOPYRROLIDIN-1-YL)ACETAMIDO]-ETHYL}-7-METHOXYNAPHTHALENE##STR14##

A mixture of 0.02 mol of 2-(7-methoxynaphth-1-yl)-ethylamine and 0.022mol of methyl (-2-oxo-pyrrolidin-1yl) acetate is heated under magneticagitation at a temperature of 80° C. for 3 hours.

The reaction medium is taken up in slightly acid water, and theprecipitate formed is spun down and recrystallized in di-n-butyl ether.

Yield: 55%

Melting point: 125°-126° C.

Spectral characteristics: Infrared: 3310 cm^(-`) vNH 3060-2820 cm⁻¹vCH(CH₂ CH₂) 1690 cm⁻¹ vCO (CON) 1630-1600 cm⁻¹ vCC (aromatic) 1030 cm⁻¹vOCH₃

¹ H Nuclear magnetic resonance, Solvent CDCl₃ : δ: 3.88 ppm, singlet,2H, NHCOCH₂ δ: 4.00 ppm, singlet, 3H, OCH₃

EXAMPLE 7: N-[2-(7-METHOXYNAPHTH-1-YL)ETHYL]-4-CHLOROBUTYRAMIDE

0.02 mol of 2-(7-methoxynaphth-1-yl)ethylamine hydrochloride isdissolved in a water/chloroform mixture. Potassium carbonate is addedand the mixture is agitated for 15 minutes in an ice bath. 0.022 mol of4-chlorobutyryl chloride is then added dropwise. The agitation ismaintained for half an hour at room temperature; then the chloroformphase is dried, and the residue is recrystallized in atoluene/cyclohexane mixture (1:1).

Yield: 93%

Melting Point: 97°-98° C.

Spectral characteristics: Infrared: 3320 cm⁻¹ vNH 1635 cm⁻¹ vCO

EXAMPLE 8: N-[2-(7-METHOXYNAPHTH-1-YL)ETHYL]-PYRROLIDIN-2-ONE

0.01 mol of sodium is dissolved in 50 ml of ethanol, and theN-[2-(7-methoxynaphth-1-yl)ethyl]chloro-4-butyramide obtained in Example7 is added under magnetic agitation. The agitation is maintained for 20minutes, and then the mixture is dried and the residue is solubilized in40 ml of anhydrous dimethylformamide. The solution is heated at boilingpoint for 7 hours, then evaporated under vaccum and the residue is takenup in ether, then filtered and dried. The residue is recrystallized inpetroleum ether.

Yield: 35%

Melting point: 60°-61° C.

Spectral characteristics: Infrared: 3060-2820 cm⁻¹ vCH 1670 cm⁻¹ vCO

EXAMPLE 9: N-[2-(7-METHOXYNAPHTH-1-YL)ETHYL)-2-BROMOACETAMIDE

The same procedure as in Example 7, replacing 4-chlorobutyryl chlorideby bromoacetyl chloride.

Melting point: 100°-101° C.

Yield: 93%

Spectral characteristics: Infrared: 3260 cm⁻¹ vNH 1635 cm⁻¹ vCO ¹ HNuclear magnetic resonance, Solvent CDCl₃ : δ: 2.83 ppm, singlet, 2H,(CH₂ Br) δ: 3.98 ppm, singlet, 3H, (OCH₃)

EXAMPLE 10: N-[2-(7-METHOXYNAPHTH-1-YL)ETHYL]-2-MORPHOLINOACETAMIDE

0.01 mol of morpholine is dissolved under magnetic agitation in 50 ml ofacetone, and 0.012 mol of triethylamine and 0.01 mol ofN-[2-(7-methoxynaphth-1-yl) ethyl]-2-bromoacetamide are added. Themixture is refluxed for 1 hour under magnetic agitation. The precipitateformed is spun down and the filtrate is evaporated. The residue is takenup in alkaline water, and the precipitate - is spun down, washed, driedand recrystallized in a toluene/cyclohexane mixture.

Spectral characteristics: Infrared: 1645 cm⁻¹ vCO

¹ H Nuclear magnetic resonance, Solvent CDCl₃ : 1 δ: 3.98 ppm, singlet,3H, OCH₃ δ: 2.92 ppm, singlet, 2H, (CO--CH₂)

Melting point: 114°-115° C.

Yield: 93%

EXAMPLE 11:N-[2-(7-METHOXYNAPHTH-1-YL)ETHYL]-2-{4-[(2,3,4-TRIMETHOXYPHENYL)METHYL]-PIPERAZIN-1-YL}ACETAMIDE HYDROCHLORIDE

The product of the title is obtained by proceeding as in the previousexample, but replacing morpholine by1-[(2,3,4-trimethoxyphenyl)methyl]piperazine. The hydrochloride isobtained by dissolving the product in acetone, bubbling a current ofhydrogen chloride gas, evaporation and recrystallization in absolutealcohol.

Spectral characteristics: Infrared: 1670 cm⁻¹ vCO

¹ H Nuclear magnetic resonance, Solvent CDCl₃ : δ: 3.99 ppm, singlet,3H, OCH₃

Melting point: 207°-208° C/

Yield: 90%

EXAMPLE 12: N-[2-(7-METHOXYNAPHTH-1-YL)ETHYL]-N-METHYLACETAMIDE

The product of the title is obtained by replacing2-(7-methoxynaphth-1-yl)ethylamine in Example 1 byN-[2-(7-methoxynaphth-1-yl) ethyl]-N-methylamine.

Spectral characteristics: Infrared: 1640 cm⁻¹ vCO

¹ H Nuclear magnetic resonance, Solvent CDCl₃ : δ: 3.98 ppm, singlet,3H, OCH₃

EXAMPLE 13: N-[2-(7-METHOXYNAPHTH-1-YL)ETHYL]-BENZAMIDE

The product of the title is obtained by replacing phenacetyl chloride inExample 2 by benzoyl chloride.

Spectral characteristics: Infrared: 1640 cm⁻¹ vCO

¹ H Nuclear magnetic resonance, Solvent CDCl₃ : δ: 3.98 ppm, singlet,3H, OCH₃

Melting point: 128°-130° C.

Yield: 94%

EXAMPLE 14: N-[2-(7-METHOXYNAPHTH-1-YL)ETHYL]-PARATOLUOYL CARBOXAMIDE

The product of the title is obtained by replacing phenylacetyl chloridein Example 2 by paratoluoyl chloride.

Spectral characteristics: Infrared: 1635 cm⁻¹ vCO

¹ H Nuclear magnetic resonance, Solvent CDCl₃ : δ: 3.95 ppm, singlet,3H, OCH₃

EXAMPLE 15: N-[2-(7-METHOXYNAPHTH-1-YL)ETHYL]-4-FLUOROBENZARIDE

The product of the title is obtained by replacing phenylacetyl chloridein Example 2 by parafluorobenzoyl chloride.

Spectral characteristics: Infrared 1635 cm⁻¹ vCO

¹ H Nuclear magnetic resonance, Solvent CDCl₃ : δ: 3.95 ppm, singlet,3H, OCH₃

EXAMPLE 16: N-[2-(7-METHOXYNAPHTH-1-YL)ETHYLI-3-TRIFLUOROMETHYLBENZAMIDE

The product of the title is obtained by replacing phenylacetyl chloridein Example 2 by 3-trifluoromethyl-benzoyl chloride.

Spectral characteristics: Infrared: 1635 cm⁻¹ vCO

¹ H Nuclear magnetic resonance, Solvent CDCl₃ : δ: 3.95 ppm, singlet,3H, OCH₃

EXAMPLE 17: N-[2-(7-METHOXYRAPHTH-1-YL)ETHYL]-3,5-DICEILOROBENZAMIDE

The product of the title is obtained by replacing phenacetyl chloride inExample 2 by 3,5-dichlorobenzoyl chloride.

Yield: 93%

Melting Point: 138° C.

EXAMPLE 18: N-[2-(7-METHOXYNAPHTH-1-YL)ETHYL]-ISONICOTINMIDE

The product of the title is obtained by replacing phenacetyl chloride inExample 2 by isonicotinoyl chloride.

Spectral characteristics: Infrared: 1635 cm⁻¹ vCO

¹ H Nuclear magnetic resonance, Solvent CDCl₃ : δ: 3.95 ppm, singlet,3H, OCH₃

EXAMPLE 19: N-[2-(7-METHOXYNAPHTH-1-YL)ETHYL]-2-THIOPHENECARBOXAMIDE

The product of the title is obtained by replacing phenylacetyl chloridein Example 2 by 2-thiophene carbonyl chloride.

Spectral characteristics: Infrared: 1635 cm⁻¹ vCO

¹ H Nuclear magnetic resonance, Solvent CDCl₃ : δ: 3.95 ppm, singlet,3H, OCH₃

EXAMPLE 20: N-[2-(7-METHOXYNAPHTH-1-YL)ETHYL]-2-QUINOXALINECARBOXAMIDE

The product of the title is obtained by replacing phenylacetyl chloridein Example 2 by 2-quinoxaloyl chloride.

Spectral characteristics: Infrared: 1635 cm⁻¹ vCO

¹ H Nuclear magnetic resonance, Solvent CDCl₃ : δ: 3.95 ppm, singlet,3H, OCH₃

EXAMPLE 21: N-[2-(7-METHOXYNAPHTH-1-YL)ETHYL]-INDOLE-CARBOXAMIDE

The product of the title is obtained by replacing phenacetyl chloride inExample 2 by 2-indolyl chloride.

Melting point: 198°-199° C.

Spectral characteristics: Infrared: 3400 cm⁻¹ vNH (indole) 3300 cm⁻¹ vNH1640 cm⁻¹ vCO

¹ H Nuclear magnetic resonance, Solvent CDCl₃ : δ: 3.98 ppm, singlet,3H, OCH₃

EXAMPLE 22: N-[2-(7-METHOXYNAPHTH-1-YL)ETHYL]-2-BENZYLAMINOACETAMIDE

The product of the title is obtained by following the same procedure asin Example 10 and by replacing morpholine by benzylamine.

Spectral characteristics: Infrared: 1635 cm⁻¹ vCO

¹ H Nuclear magnetic resonance, Solvent CDCl₃ : δ: 3.95 ppm, singlet,3H, OCH₃

EXAMPLE 23:N-[2-(7-METHOXYNAPHTH-1-YL)ETHYL]-2-(N',N'-DIETHYL)AMINOACETAMIDE

The product of the title is obtained by following the same procedure asin Example 10, but replacing morpholine by N,N-diethylamine.

Spectral characteristics: Infrared: 1635 cm⁻¹ vCO

¹ H Nuclear magnetic resonance, Solvent CDCl₃ : δ: 3.95 ppm, singlet,3H, OCH₃

EXAMPLE 24: N-[2-(7-METHOXYNAPHTH-1-YL)ETRYL]-2-ANINOACETAMIDEHYDROCHIDRIDE

0.012 mol of hexamethylenetetramine is dissolved under magneticagitation in 15 ml of chloroform, and 0.01 mol ofN-[2-(7-methoxynaphth-1-yl)ethyl]-2-bromoacetamide obtained in Example 9dissolved in 20 ml of chloroform are introduced. The mixture is refluxedfor 100 hours, spun down and dried. The precipitate is introduced into aground glass flask and 150 ml of alcohol and 30 ml of concentratedhydrochloric acid are added. The mixture is refluxed for two hours, andthen the solvent is evaporated and the residue is recrystallized inalcohol at 90° C.

Spectral characteristics: Infrared: 1635 cm⁻¹ vCO

¹ H Nuclear magnetic resonance, Solvent CDCl₃ : δ: 3.95 ppm, singlet,3H, OCH₃

EXAMPLE 25: N-[2-(7-METHOXYNAPHTH-1-YL)ETHYL]2-[4-(4-FLUOROPHENYL)PIPERAZIN-1-YL]-ACETAMIDE

The product of the title is obtained by f ollowing the same procedure asin Example 10, but replacing morpholine by 1-(4-fluorophenyl)piperazine.

EXAMPLE 26:N-[2-(7-METHOXYNAPHTH-1-YL)ETHYL]-2-[4-(3-TRIFLUOROMETHYLPHENYL)PIPERAZIN-1-YL]ACETAMIDE

The product of the title is obtained by f ollowing the same procedure asin Example 10, but replacing morpholine by1-(3-trifluoromethylphenyl)piperazine.

EXAMPLE 27: N-[2-(7-METHOXYNAPETH-1-YL)ETHYL]-BUTYRAMIDE

The product of the title is obtained by following the same procedure asin Example 1, but replacing acetyl chloride by butyryl chloride.

Melting point: 99° C.

EXAMPLE 28: N-[2-(7-METHOXYNAPHTH-1-YL)ETHYL]-4-IMIDAZOLYLACETAMIDE

0.01 mol of 2-(7-methoxynaphth-1-yl)ethylamine hydrochloride isdissolved in 60 ml of a chloroform/water mixture, and 0.025 mol ofpotassium carbonate is added under magnetic agitation. The mixture iscooled, and 0.012 mol of 4-imidazoleacetyl chloride hydrochloride isadded dropwise. The agitation is maintained for 30 minutes at roomtemperature and the chloroform phase is evaporated to dryness. Theresidue is then recrystallized.

Yield: 67%

Spectral characteristics: Infrared: 1640 cm⁻ vCO

¹ H Nuclear magnetic resonance, Solvent CDCl₃ δ=3.91 ppm, singlet, 1H,OCH.sub. 3 PG,21

EXAMPLE 29:N-[2-(7-METHOXYNAPHTH-1-YL)ETHYL]-2-IMIDAZOLINONE-4-CARBOXAMIDE

The product of the title is obtained by f ollowing the same procedure asin Example 1, but replacing acetyl chloride by2-imidazolinone-4-carboxyl chloride.

Yield: 55%

Spectral characteristics:

¹ H Nuclear magnetic resonance, Solvent CDCl₃ δ=3.89 ppm, singlet, 1H,OCH₃

EXAMPLE 30: N-[2-(7-METHOXYNAPHTH-1-YL)ETHYL]-CYCLOBEXANECARBOXAMIDE (R₂=cyclohexyl)

The product of the title is obtained by following the same procedure asin Example 1, but replacing acetyl chloride by cyclohexanecarboxylchloride.

Recrystallizing solvent: cyclohexane

Melting point: 105°-106° C.

EXAMPLE 31: N-[2-(7-METHOXYNAPHTH-1-YL)ETHYL]-CYCLOPROPANECARBOXAMIDE(R₂ =cyclopropyl)

The product of the title is obtained by following the same procedure asin Example 1, but replacing acetyl chloride with cyclopropylcarboxylchloride.

Crystallizing solvent: cyclohexane

Melting point: 91°-92° C.

EXAMPLE 32: N-[2-(7-METHOXYNAPHTH-1-YL)ETHYL]-IODOACETAMIDE

The product of the title is obtained by treating theN-[2-(7-methoxynaphth-1-yl)ethyl]-2-bromoacetamide obtained in Example 9with potassium iodide.

Recrystallizing solvent: ethanol

Melting point: 110°-112° C.

EXAMPLE 33: N-[2-(7-METHOXYNAPHTH-1-YL)ETHYL]-FORMAMIDE

0.01 mol of 2-(7-methoxynaphth-1-yl)ethylamine and 0.02 mol of formicacid are placed in a porcelain crucible, and heated at 120° C. until adry residue is obtained. This is recrystallized.

Melting Point: 93° C.

Spectral characteristics:

Nuclear magnetic resonance:

δ: 4.05 ppm, singlet, 3H, OCH₃

EXAMPLE 34: N-[2-(7-METHOXYNAPHTH-1-YL)ETHYL]-CYCLOBUTANECARBOXAMIDE

The product of the title is obtained by following the same procedure asin Example 1, but replacing acetyl chloride by cyclobutanecarboxylchloride.

EXAMPLE 35: N-[2-(7-METHOXYNAPHTH-1-YL)ETHYL]-CYCLOPENTANECARBOXAMIDE

The product of the title is obtained by following the same procedure asin Example 1, but replacing acetyl chloride by cyclopentanecarboxylchloride.

Proceeding according to the preceding examples, one also obtains:

N-[2-(7-METHOXYNAPHTH-1-YL)ETHYL]-4-BROMOBUTYRAMIDE

N-[2-(7-METHOXYNAPHTH-1-YL)ETHYL]-5-BROMOPENTANAMIDE

N-[2-(7-METHOXYNAPHTH-1-YL)ETHYL]-3-BROMOPROPIONAMIDE

N-[2-(7-METHOXYNAPHTH-1-YL)ETHYL]-3-MORPHOLINOPROPIONAMIDE

N-[2-(7-METHOXYNAPHTH-1-YL)ETHYL]-3-MORPHOLINOBUTYRAMIDE

N-[2-(7-METHOXYNAPHTH-1-YL)ETHYL]-4-{4-[(2,3,4-TRIMETHOXY-PHENYL)METHYL]-PIPERAZIN-1-YL}BUTYRAMIDE

N-[2-(7-METHOXYNAPHTH-1-YL)ETHYL]-3-{4-[(2,3,4-TRIMETHOXY-PHENYL)METHYL]-PIPERAZIN-1-YL}PROPIONAMIDE

N-[2-(7-METHOXYNAPHTH-1-YL)ETHYL]PIPERIDIN-2-ONE

N-[2-(7-METHOXYNAPHTH-1-YL)ETHYL]-2-BROMOPROPIONAMIDE

N-[2-(7-METHOXYNAPHTH-1-YL)ETHYL]-2-{4-[(2,3,4-TRIMETHOXY-PHENYL)METHYL]PIPERAZIN-1-YL}PROPIONAMIDE

By replacing 2-(7-methoxynaphth-1-yl)ethylamine in the precedingexamples by 2-(6-methoxynaphth-1-yl)-ethylamine or by2-(5-methoxynaphth-1-yl)ethylamine, the products of the precedingexamples methoxylated at position 6 or 5 on the naphthalene respectivelyare obtained in place of the derivatives methoxylated at position 7.

By replacing 2-(7-methoxynaphth-1-yl)ethylamine in the precedingexamples by 2-(7-methoxynaphth-2-yl) ethylamine, one obtains:

N-[2-(7-METHOXYNAPHTH-2-YL)ETHYL]ACETAMIDE

N-[2-(7-METHOXYNAPHTH-2-YL)ETHYL]PHENYLACETAMIDE

N-[2-(7-METHOXYNAPHTH-2-YL)ETHYL]ISOBUTYRAMIDE

N-[2-(7-METHOXYNAPHTH-2-YL)ETHYL]PROPIONAMIDE

N-[2-(7-METHOXYNAPHTH-2-YL)ETHYL]PENTANAMIDE

N-[2-(7-METHOXYNAPHTH-2-YL)ETHYL]-(2-OXOPYRROLIDIN-1-YL)-ACETAMIDE

N-[2-(7-METHOXYNAPHTH-2-YL)ETHYL]-4-CHLOROBUTYRAMIDE

N-[2-(7-METHOXYNAPHTH-2-YL)ETHYL]PYRROLIDIN-2-ONE

N-[2-(7-METHOXYNAPHTH-2-YL)ETHYL]-2-BROMOACETAMIDE

N-[2-(7-METHOXYNAPHTH-2-YL)ETHYL]-2-MORPHOLINOACETAMIDE

N-[2-(7-METHOXYNAPHTH-2-YL)ETHYL]-2-{4-[(2,3,4-TRIMETHOXY-PHENYL)METHYL]PIPERAZIN-1-YL}ACETAMIDE HYDROCHLORIDE

N-[2-(7-METHOXYNAPHTH-2-YL)ETHYL]-N-METHYLACETAMIDE

N-[2-(7-METHOXYNAPHTH-2-YL)ETHYL]BENZAMIDE

N-[2-(7-METHOXYNAPHTH-2-YL)ETHYL]PARATOLUOYLCARBOXAMIDE

N-[2-(7-METHOXYNAPHTH-2-YL)ETHYL]-4-FLUOROBENZAMIDE

N-[2-(7-METHOXYNAPHTH-2-YL)ETHYL]-3-TRIFLUOROMETHYLBENZAMIDE

N-[2-(7-METHOXYNAPHTH-2-YL)ETHYL]-3,5-DICHLOROBENZAMIDE

N-[2-(7-METHOXYNAPHTH-2-YL)ETHYL]ISONICOTINAMIDE

N-[2-(7-METHOXYNAPHTH-2-YL)ETHYL]-2-THIOPHENECARBOXAMIDE

N-[2-(7-METHOXYNAPHTH-2-YL)ETHYL]-2-QUINOXALINECARBOXAMIDE

N-[2-(7-METHOXYNAPHTB-2-YL)ETHYL]INDOL-2-YLCARBOXAMIDE

N-[2-(7-METHOXYNAPHTH-2-YL)ETHYL]-2-BENZYLAMINOACETAMIDE

N-[2-(7-METHOXYNAPHTH-2-YL)ETHYL]-2-(N',N'-DIETHYL)AMINOACETAMIDE

N-[2-(7-METHOXYNAPHTH-2-YL)ETHYL]-2-AMINOACETAMIDE

N-[2-(7-METHOXYNAPHTH-2-YL)ETHYL]-2-[4-(4-FLUOROPHENYL)-PIPERAZIN-1-YL]ACETAMIDE

N-[2-(7-METHOXYNAPHTH-2-YL)ETHYL]-2-[4-(3-TRIFLUOROMETHYLPHENYL)PIPERAZIN-1-YL]ACETAMIDE

N-[2-(7-METHOXYNAPHTH-2-YL)ETHYL]BUTYRAMIDE

N-[2-(7-METHOXYNAPHTH-2-YL)ETHYL]-4-IMIDAZOLYLACETAMIDE

N-[2-(7-METHOXYNAPHTH-2-YL)ETHYL]-2-IMIDAZOLINONE-4-CARBOXAMIDE

N-[2-(7-METHOXYNAPHTH-2-YL)ETHYL]CYCLOBEXANECARBOXAMIDE

N-[2-(7-METHOXYNAPHTH-2-YL)ETHYL]CYCLOPROPANECARBOXAMIDE

N-[2-(7-METHOXYNAPHTH-2-YL)ETHYL]IODOACETAMIDE

N-[2-(7-METHOXYNAPHTH-2-YL)ETHYL]FORMAMIDE

N-[2-(7-METHOXYNAPHTH-2-YL)ETHYL]CYCLOBUTANECARBOXAMIDE

N-[2-(7-METHOXYNAPHTH-2-YL)ETHYL]CYCLOPENTANECARBOXAMIDE

If in these syntheses 2-(7-methoxynaphth-2-yl)-ethylamine is replaced by2-(6-methoxynaphth-2-yl)-ethylamine, isomers of the preceding productsare obtained with the methoxy group at position 6.

PHARMACOLOGICAL STUDY OF THE COMPOUNDS OF THE INVENTION Example A: Studyof Acute Toxicity

Acute toxicity was estimated after oral administration to groups of 8mice (26±2 grams). The animals were observed at regular intervals duringthe course of the first day, and daily for 2 weeks following treatment.The LD50 bringing about the death of 50% of the animals was evaluated.

The LD50 of the products tested is greater than 1000 mg.kg⁻¹ for most ofthe compounds studied, which indicates that the compounds of theinvention have low toxicity.

Example B: Measurement of Activity

The animals were placed in plexiglass boxes equipped with photoelectriccells placed in a darkened environment. Six animals were tested at thesame time, and the number of interruptions of the photoelectric beams byeach animal was recorded by computer during one hour.

The compounds tested were administered intraperitoneally immediatelybefore placing the animals in the cages.

The compounds of the invention decreased the activity of the animals.

Example C: The Four Plate Test

The products of the invention were administered intra-esophageally togroups of 10 mice. One group received acacia syrup. 30 minutes afteradministering the products being tested, the animals were placed incages, the floors of which were made up of 4 metal plates. Each time ananimal passes from one plate to another it receives a mild electricshock (0.35 mA). The number of times the mice passed from one plate toanother were recorded for one minute. After administration, thecompounds of the invention significantly increased the number of timesthat mice passed from one plate to another, showing the anxiolyticactivity of these derivatives of the invention.

Example D: The activity of the Products of the Invention of the IschemicMicrocirculation

The experimental study was performed on the cremaster muscles of maleSprague Dawley rats after ligation of the common iliac artery.

The muscles were placed in a transparent chamber perfused with abicarbonate buffer solution equilibrated with a gaseous mixture of CO₂/N₂ (5/95%). The speed of the erythrocytes and the diameter of the firstor second order arterioles irrigating the cremaster were measured, andthe arteriolar blood flow was calculated. Identical information wasobtained for four different types of vein.

The same type of measurement was made simultaneously:

on the normal perfused cremaster,

on ligatured cremaster, i.e. the ischemic cremaster, 2, 7, 14 and 21days after ligature.

Two groups of animals were studied:

an untreated control group,

a group treated per os with a product of the invention at the rate of0.1 mg.kg⁻¹ per day.

No difference was noted in the treated animals in comparison with thecontrols in the velocity of the erythrocytes, nor in the diameter of theblood vessels in the normally irrigated cremaster muscles.

On the other hand, in the ischemic cremaster muscle the mean diameter ofthe arterioles was better in the treated animals than in the controls.The velocity of the erythrocytes was normalized by treatment for 21days.

In fact, in the treated animals the velocity of the erythrocytes and theblood flow measured 7 days after ligature did not differ significantlyfrom the values obtained in the non-ischemic cremaster. These resultswere obtained without modifying arterial blood pressure.

These results indicate that long-term treatment with a compound of theinvention improves the microcirculation and irrigation with blood ofischemic areas.

Example E: Stimulation of the Immune Response

Groups of 6 mice were administered sheep erythrocytes. These groups ofmice were then treated subcutaneously with the compounds of theinvention for 6 days, and a control group was treated with a placebo.The mice were then left alone for 4 weeks and then received a repeatinjection of sheep erythrocytes without receiving any moreadministrations of a product of the invention. The immune response wasevaluated 3 days after the repeat injection. It was significantlyenhanced in the groups treated with the compounds of the invention.

Example F: Inhibition of Ovulation

Adult female rats with regular 4-day cycles were used.

Vaginal swabs were taken daily and the rats were selected after they -showed at least two consecutive cycles of four days.

Each cycle is made up of two days of diestrus, one day of proestrus andone day of estrus.

In the afternoon of the day of proestrus, luteinizing hormone isreleased into the blood by the hypophysis. This hormone inducesovulation, which is indicated by the presence of ova in the oviduct onthe day of estrus.

The compounds of the invention were administered orally at midday on theday of estrus. The treated and control rats were sacrificed on the dayof estrus and the oviducts were examined. A significant percentagedecrease in the number of ova was noted in the oviducts of treated rats.

Example G: Demonstration of Analgesic Activity

The effect on pain was studied in mice (23-25 g) according to a protocolderived from the technique described by SIEGMUND (SIEGMUND E. A., CADMUSR. A. & GOLU: J. Pharm. Exp. Ther. 119, 1874 (1954)). Mice divided byrandomization into groups of 12 animals received the treatment orally(excipient in the case of controls) 1 hour before intraperitonealinjection of an aqueous alcoholic solution of phenyl-p-benzoquinone(Sigma) at 0.02%. Stretching movements were counted between the 5th and10th minute after the injection.

It appeared that certain compounds of the invention possess analgesicactivity.

Example H: Potentialization of Barbiturate-Induced Sleep

Mice (22-25 g) were injected intraperitoneally with pentobarbital at 50mg.kg⁻¹. The time of appearance and the duration of sleep were measured.It was recognized that the animals were asleep when they lost therighting reflex. The, compounds to be tested were administeredintraperitoneally 30 minutes before the barbiturate injection. Certainproducts of the invention increased the duration of sleep-induced bypentobarbital.

Example I: Test of Binding to Melatonin Receptors

Binding of compounds of the invention to melatonin receptors was carriedout according to conventional techniques. It appears that the compoundsof the invention bind very specifically to melatonin receptors with anaffinity greater than for melatonxn itself. The most beneficial have aK_(d) of 5.5×10⁻¹³, while melatonin itself possesses a K_(d) of6.3×10⁻¹¹, which means that certain products of the invention have aselective affinity for melatonin receptors which is 100 times greaterthan for melatonin itself.

Example J: Study of Blood Glucose-Lowering Activity

Male KK mice were placed in cages at the age of eight weeks. They wereused for the experiment when their weight was greater than 40 grams atthe age of 4-5 months.

The compound of the invention was suspended in acacia syrup. Eachcompound tested was administered orally 18 hours before blood sampling.

Blood was collected by sampling from the caudal vein in a hematocrittube, and then centrifuged. The plasma was collected and the bloodglucose concentration was determined.

It appears that certain compounds of the invention significantlydecrease blood glucose.

Example K: Pharmaceutical Composition: Tablets

Tablets containing 50 mg of N-[2-(7-methoxynaphth-1-yl) ethyl]butyramide

    ______________________________________                                        N-[2-(7-methoxynaphth-1-yl)ethyl]butyramide                                                             50 g                                                Wheat starch              15 g                                                Corn starch               15 g                                                Lactose                   15 g                                                Magnesium stearate         2 g                                                Silica                     1 g                                                Hydroxypropylcellulose     2 g                                                ______________________________________                                    

We claim:
 1. A compound of formula (I): ##STR15## in which: A represents##STR16## R represents linear or branched lower alkyl, RO and A beingsubstituted on different rings,R₁ represents hydrogen or linear orbranched lower alkyl, and R₂ represents aryl or lower aralkyl or aryl orlower arylalkyl substituted by one or more radicals selected from thegroup consisting of lower alkyl, lower alkoxy, trifluoromethyl andhalogen and where aryl means phenyl or naphthyl, or the optical isomers,epimers or diastereoisomers thereof and addition salts thereof with apharmaceutically-acceptable acid, and that the terms lower alkyl andlower alkoxy as used herein mean such a group having 1 to 6 carbon atomsinclusive.
 2. A compound as claimed in claim 1, in which the OR group isin position 7, or diastereoisomers thereof or addition salts thereofwith a pharmaceutically-acceptable acid.
 3. a compound as claimed inclaim 1, in which R₂ represents:aryl or lower arylalkyl unsubstituted orsubstituted by one or more chlorine atoms or groups chosen from amonglower alkyl, lower alkoxy, and trifluoromethyl, or diastereoisomersthereof or addition salts thereof with a pharmaceutically-acceptableacid.
 4. A compound as claimed in claim 1, in which the OR group is inposition 7, R₁ represents hydrogen and R₂ represents aryl or lowerarylalkyl unsubstituted or substituted by one or more halogen atoms, ordiastereoisomers thereof.
 5. A compound as claimed in claim 1, which isN-[2-(7-methoxynaphth-1-yl) ethyl]benzamide.
 6. A compound as claimed inclaim 1, which is N-[2-(7-methoxynaphth-1-yl)ethyl]3,5-dichlorobenzamide.
 7. A pharmaceutical composition useful fortreating melatoninergic disorders containing as active ingredient aneffective amount of at least one compound as claimed in claim 1 incombination with a pharmaceutically-acceptable inert exciipient orvehicle.
 8. A method for treating a living animal afflicted with atreatable disorder of the melatoninergic system comprising the step ofadministering to the said living animal an amount of a compound of claim1 which is effective for alleviation of the said condition.